Alkylation process for preparing azetidinone compound and starting compound therefor

ABSTRACT

Novel process for preparing azetidinone compound of the formula [III]: ##STR1## wherein R 1  is H or lower alkyl, R 2  and R 3  combine together with the adjacent nitrogen to form heterocyclic group, and R 4  is protected or unprotected hydroxy-substituted lower alkyl, which comprises reacting an alkanamide compound of the formula [I]: ##STR2## wherein R 1 , R 2  and R 3  are the same as defined above, with a compound of the formula [II]: ##STR3## wherein L 1  is a leaving group and R 4  is the same as defined above, in the presence of a base, said compound [III] being useful as synthetic intermediate for 1-methylcarbapenem derivative having excellent antibacterial activity.

The present invention relates to a novel process for preparing anazetidinone compound which is useful as a synthetic intermediate for a1β-methylcarbapenem derivative having an antibacterial activity, and anovel starting compound therefor.

PRIOR ART

1β-Methylcarbapenem derivatives have been of great interests for theirexcellent antibacterial activities against a wide range ofmicroorganisms including Gram positive and Gram negative bacteria,especially against Cephem-resistant bacteria, and their excellentstabilities in the human bodies.

Said 1β-methylcarbapenem derivatives have been synthesized by variousprocesses up to now. In these processes, the azetidinone compound havinga p-methyl group at the 1'-position of the 4-side chain of the formula:##STR4## wherein R is a protected or unprotected hydroxy-substitutedlower alkyl group, is especially important synthetic intermediate, whichis prepared by removing 1'-hydrogen atom of the acetic acid moiety atthe 4-position with a strong base, followed by introducing a methylgroup to the product [cf. Heterocycles, 21, 29 (1984)].

However, it is difficult to stereoselectively obtain compounds having1'-substituent with β-configuration of the 4-side chain by this process,and therefore, various processes for preparing stereoselectively thecompound having 1'-substituent with β-configuration have been reported.

For example, Fuentes et al. suggest a process of reacting4-acetoxy-azetidinone compound with a specific propionimide in thepresence of a complex reagent of a specific base and a Lewis acid (e.g.tin triflate--ethylpiperidine-zinc bromide, diethylborantriflate-diisopropylethylamine-zinc bromide, etc.) (cf. L. M. Fuentes etal., J. Am. Chem. Soc., 108, 4675 (1986)). The similar process toFuentes's is also reported by Nagao et al. (cf. Y. NAGAO et al., J. Am.Chem. Soc., 108, 4673 (1986)).

Besides, there is also reported a process of reacting4-acetoxy-azetidinone compound with propionic acid thiol ester orpropionic acid ester in the presence of a complex reagent of a base anda Lewis acid (cf. C. U. Kim et al., Tetrahedron Lett., 28, 507 (1978),A. Martel et al., Can. J. Chem., 66, 1537 (1988), and M. Endo, Can. J.Chem., 65, 2140 (1987)).

However, a complex reagent of a base and a Lewis acid is essential inthese processes, and there are obtained as side-products undesirablecompounds having the 1'-substituent with α-configuration, and hence, theyield and purity of the desired 1'-β-compound is insufficient.

BRIEF DESCRIPTION OF INVENTION

An object of the present invention is to provide a novel process forstereoselectively preparing azetidinone compound having the1'-substituent with β-configuration which is useful as a syntheticintermediate for 1β-methylcarbapenem derivative having an antibacterialactivity. Another object of the present invention is to provide a novelsynthetic intermediate therefor.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors have intensively studied a novel process forpreparing a synthetic intermediate with desired 1'-β-configuration forcarbapenem antibacterial agents without the defects of the conventionalprocesses, and finally have found that the desired 1'-β-azetidinonecompound is obtained by reacting an azetidinone compound having aleaving group with an alkanamide in the presence of a specific basewithout using a Lewis acid which is essential in the conventionalprocesses.

That is, the present invention provides a novel process for preparing anazetidinone compound of the formula [III]: ##STR5## wherein R¹ ishydrogen atom or a lower alkyl group, R² and R³ combine together withthe adjacent nitrogen atom to form a heterocyclic group, and R⁴ is aprotected or unprotected hydroxy-substituted lower alkyl group, whichcomprises reacting an alkanamide of the formula [I]: ##STR6## whereinR¹, R² and R³ are the same as defined above, with a compound of theformula [II]: ##STR7## wherein L¹ is a leaving group and R⁴ is the sameas defined above, in the presence of a base.

The present invention also provides a novel compound of the formula[I-A]: ##STR8## wherein Ring B is a substituted or unsubstituted benzenering, X is oxygen atom or sulfur atom, Y is oxygen atom, sulfur atom, aprotected or unprotected imino group or methylene group, Z¹ and Z² arethe same or different and each hydrogen atom, a substituted orunsubstituted alkyl group, a substituted or unsubstituted cycloalkylgroup, an aryl group or an aralkyl group, or both combine at the endthereof to form a substituted or unsubstituted alkylene group having 4to 7 carbon atoms, and R¹ is the same as defined above, which is astarting compound for the compound [III].

The heterocyclic group of the formula --N(R²)(R³) in the alkanamide ofthe formula [I] includes a 5- or 6-membered heterocyclic group havingnitrogen atom or having oxygen atom or sulfur atom in addition tonitrogen atom, for example, groups disclosed in Japanese Patent FirstPublication (Kokai) Nos. 10765/1988, 252786/1987, 284176/1988,292269/1990, 788/1990, 275267/1986, 169781/1987, 77384/1987,170377/1988, 246550/1987, 65195/1994, etc, i.e. groups of the formula:##STR9## wherein X¹ is oxygen atom or sulfur atom, Y¹ is oxygen atom,sulfur atom, methylene group or imino group substituted by an alkylgroup or an aryl group, R¹¹, R¹², R¹³ and R⁴ are the same or differentand each hydrogen atom, a C₁ -C₅ lower alkyl group, cyano group, analkoxycarbonyl group, an aralkyl group, or an aryl group, or R¹¹ and R¹²combine together to form a C₂ -C₆ alkylene chain, and simultaneously orindependently R¹³ and R¹⁴ combine together to form a C₂ -C₆ alkylenechain, or R¹¹, R¹², R¹³ and R¹⁴ combine together with the adjacent twocarbon atoms to form a substituted or unsubstituted aromatic cyclicgroup.

The other examples of said heterocyclic groups are the groups disclosedin Japanese Patent Application Nos. 303662/1992, 111460/1993,283148/1993, etc., i.e. groups of the formula: ##STR10## wherein X, Y,Z¹ and Z² are the same as defined above, Ring A is the same substitutedor unsubstituted benzene ring as defined for Ring B, or a substituted orunsubstituted heterocyclic ring having 1 to 4 hetero atoms selected fromoxygen atom, sulfur atom and nitrogen atom, or groups of the formula:##STR11## wherein X, Y and Ring A are the same as defined above.

Among the above mentioned heterocyclic rings, the suitable examples ofRing A are heterocyclic rings of the following formulae: ##STR12##wherein Y is the same as defined above.

In the present invention, the substituents on Ring A and Ring B arepreferably a halogen atom, a lower alkyl group, a lower alkoxy group,and an aryl group, and Ring A and Ring B may have one to foursubstituents which are the same or different. The group represented byR⁴ is preferably a protected or unprotected 1-hydroxyethyl group, andthe protecting group for said hydroxy group may be any ones which caneasily be removed by a conventional method, for example, a loweralkoxycarbonyl group, a halogeno-lower alkoxycarbonyl group, asubstituted or unsubstituted phenyl-lower alkyl group (e.g. benzyl groupwhich may optionally be substituted by nitro group or a lower alkoxygroup), a tri-lower alkylsilyl group, a substituted or unsubstitutedphenyl-lower alkoxycarbonyl group (e.g. benzyloxycarbonyl group whichmay optionally be substituted by nitro group or a lower alkoxy group),and the like.

The alkyl group for Z¹, Z², R¹¹, R¹², R¹³ and R¹⁴ includes alkyl groupshaving 1 to 20 carbon atoms, preferably ones having 1 to 15 carbonatoms. The cycloalkyl group includes, for example, ones having 4 to 7carbon atoms, and the aryl group includes, for example, a substituted orunsubstituted phenyl group. The aralkyl group includes, for example, alower alkyl group substituted by a substituted or unsubstituted phenylgroup. The substituents for alkyl group, cycloalkyl group, and thesubstituents on the phenyl group in the aryl group or in the aralkylgroup are preferably a lower alkoxy group, a halogen atom, a protectedor unprotected amino group.

The protecting group for amino group, or the protecting group for iminogroup represented by Y includes any group which is conventionally usedas a protecting group in the field of Peptide Chemistry, and theexamples of the protecting group are preferably a lower alkyl group, anacyl group (e.g. a lower alkanoyl group, a lower alkoxycarbonyl group, asubstituted or unsubstituted phenylcarbonyl group, a substituted orunsubstituted phenyl-lower alkoxycarbonyl group).

Among the starting compounds [I], the compound of the formula [I-A] is anovel compound. The compound [I-A] of the present invention isstructurally quite different from the above-mentioned known compound inthat the amido moiety (hereinafter referred to as "supporting group") ofthe compound [I-A] of the present invention is the benzenering-condensed 6-membered heterocyclic group, while the known supportinggroup is the 5-membered heterocyclic groups such as thiozolidine oroxazolidine. In the compound [I-A] of the present invention, any grouphaving partial structure of the formula: ##STR13## wherein the symbolsare the same as defined above, can be used as the supporting group ofthe present invention, and therefore, when Ring B and/or Y havesubstituents, said substituents may be any one which does notdisadvantageously affect the reaction. However, the compound [I-A]wherein Ring B is unsubstituted benzene ring, X and Y are both oxygenatom, Z¹ and Z² are a substituted or unsubstituted alkyl group, or bothcombine at the end thereof to form a unsubstituted alkylene group having4 to 7 carbon atoms are more preferable.

The base used in the reaction of the alkanamide compound [I] and thecompound [II] to give the compound [III] includes any conventionalorganic and inorganic bases, but strong bases are more preferable. Thepreferable strong base is a base having enough basicity to make anenolate by removing hydrogen atom at α-position of the alkanamidecompound [I] and the more preferable base is a base having basicity ofpKb<-10. Examples of a base include an alkali metal salt or alkalineearth metal salt of amines (e.g. alkali metal bis(tri-loweralkylsilyl)amide), or an alkali metal salt or alkaline earth metal saltof alcohols, more particularly lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithiumdiisopropylamide, sodium amide, sodium methoxide, sodium ethoxide,potassium t-butoxide, and the like.

The reaction of the alkanamide compound [I] and the compound [II] ispreferably carried out in an appropriate inert solvent such as ethers(e.g. tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane,diisopropyl ether, etc.), aromatic hydrogen carbons (e.g. toluene,xylene, etc.), and the like, and more preferably carried out intetrahydrofuran. The leaving group represented by L¹ in the compound[II] may be any conventional leaving groups which can easily be removedduring the reaction with the alkanamide compound [I], for example, anacyloxy group, a lower alkylsulfonyloxy group, an arylsulfonyloxy group,a lower alkylsulfonyl group, an arylsulfonyl group, an arylthio group, ahalogen atom, and the like, and an acyloxy group is more preferable.

The alkanamide compound [I] may be used in an amount of 1 to 1.5 moles,preferably 1.1 to 1.3 moles, per one mole of the compound [II]. The basemay be used in an amount of 1 to 2 moles, preferable 1.2 to 1.5 moles,per one mole of the compound [II]. The reaction is usually carried outat a temperature of -80° C. to 10° C., preferably at -60° C. to -30° C.

The alkanamide compound [I] including the novel starting compound [I-A]is prepared by reacting a compound of the formula [IV]: ##STR14##wherein R² and R³ are the same as defined above, with a compound of theformula [V]:

    R.sup.1 CH.sub.2 COOH                                      [V]

wherein R¹ is the same as defined above, or a reactive derivativethereof.

In preparing the novel starting compound [I-A] by the above reaction, abenzene compound of the formula [IV-1]: ##STR15## wherein Ring B, X, Y,Z¹ and Z² are the same as defined above, is used as the compound [IV].

The reaction of the compound [IV] and the compound [V] is carried out inan appropriate solvent in the presence of a dehydrating agent. Thedehydrating agent is preferably carbonyldiimidazole,dicyclohexylcarbodiimide, N-hydroxysuccinimide, 1-hydroxybenzotriazole,and the like, and the solvent is preferably ether, methylene chloride,tetrahydrofuran, acetonitrile, and the like. The reaction is carried outat a temperature of -30° C. to 70° C., preferably at 0° C. to 30° C.

The reaction of the compound [IV] and a reactive derivative of thecompound [V] is carried out in an appropriate solvent in the presence orabsence of an acid acceptor. The reactive derivative is preferably anacid halide or an acid anhydride of the compound [V]. The acid acceptorincludes, for example, an alkali metal hydride, an alkali metal, or anorganic base such as a lower alkyl lithium compound, an aryl lithiumcompound, pyridine, a di-lower alkyl-aniline, a tri-lower alkylamine,etc. The solvent is preferably tetrahydrofuran, diethyl ether, benzene,toluene, dichloromethane, chloroform, and the like. The reaction iscarried out at a temperature of -80° C. to 50° C., preferably at atemperature of -20° C. to 30° C.

The azetidinone compound [III] prepared by the present process isconverted into an azetidinonealkanoic acid of the formula [VI]:##STR16## wherein R¹ and R⁴ are the same as defined above, by subjectingit to hydrolysis, which is a useful intermediate for carbapenemcompounds.

The hydrolysis is carried out by a conventional method, but preferablyin the presence of hydrogen peroxide and an alkali metal hydroxide in anappropriate solvent. The solvent includes, for example, a mixed solventof an organic solvent (e.g. dioxane, tetrahydrofuran, dimethylformamide,methanol, etc.) and water, and the mixed solvent of tetrahydrofuran andwater is more preferable. The alkali metal hydroxide includes, forexample, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.,and lithium hydroxide is more preferable. Besides, hydrogen peroxide maybe used in an amount of 1 to 10 moles, preferably 6 to 8 moles, per onemole of the azetidinone compound [III]. The alkali metal hydroxide maybe used in an amount of 1 to 5 moles, preferably 2 to 3 moles, per onemole of the azetidinone compound [III]. The reaction is carried out at atemperature of -10° C. to 30° C., preferably at -5° C. to 5° C.

The azetidinone compound [III] can be converted into the desired1β-methylcarbapenem antibacterial agent. That is, the azetidinonecompound [III] is reacted with an acetic acid compound of the formula[VII]:

    L.sup.2 --CH.sub.2 --COOR.sup.5                            [VII]

wherein R⁵ is hydrogen atom or an ester residue, and L² is a leavinggroup, to give an N-substituted azetidinone compound of the formula[VIII]: ##STR17## wherein R¹, R², R³, R⁴ and R⁵ are the same as definedabove, followed by subjecting the compound [VIII] or a salt thereof tointramolecular cyclization, esterifying the product to give a1β-methyl-2-oxycarbapenem derivative of the formula [IX]: ##STR18##wherein a group of formula --OA is an esterified hydroxy group, and R¹,R⁴ and R⁵ are the same as defined above, reacting the compound [IX] witha thiol compound of the formula [X]:

    H--SR.sup.6                                                [IX]

wherein R⁶ is an organic group, or a salt thereof, and when R⁴ is aprotected hydroxy-substituted lower alkyl group, and/or R⁵ is an esterresidue, if necessary, further by removing the protecting group for saidhydroxy-substituted lower alkyl group and/or said ester residue to givea 1β-methyl-carbapenem derivative of the formula [XI]: ##STR19## whereinR⁴¹ is a protected or unprotected hydroxy-substituted lower alkyl group,R⁵¹ is hydrogen atom or an ester residue, and R¹ and R⁶ are the same asdefined above.

The ester residue for R⁵ in the acetic acid compound [VII], theN-substituted azetidinone compound [VIII] and the1β-methyl-2-oxycarbapenem derivative [IX], and for R⁵¹ in the1β-methylcarbapenem derivative [XI] is, for example, an ester residuewhich may be metabolized or hydrolyzed in the human body, or an esterresidue which can be a protecting group for carboxyl group.

The ester residue which may be metabolized or hydrolyzed in the humanbody includes, for example, groups of the formulae: --Q--OCOR⁷,--Q--OCO₂ R⁷ or --Q--O--R⁷ (wherein Q is a lower alkylene group, R⁷ is alower alkyl group, a cycloalkyl group, a lower alkenoyl group, a loweralkoxy-lower alkyl group, and a lower alkanoyloxy-lower alkyl group)such as a lower alkanoyloxy-lower alkyl group, acycloalkylcarbonyloxy-lower alkyl group, a lower alkenoyloxy-lower alkylgroup, a lower alkoxy-lower alkanoyloxy-lower alkyl group, a loweralkanoyloxy-lower alkoxy-lower alkyl group, a lower alkoxy-lower alkylgroup, a lower alkoxy-lower alkoxy-lower alkyl group, a loweralkoxycarbonyloxy-lower alkyl group, a lower alkoxy-loweralkoxycarbonyloxy-lower alkyl group.

On the other hand, the ester residue which can be a protecting group forcarboxyl group may be any ones which can easily be removed by aconventional method, for example, a lower alkyl group, a lower alkenylgroup, a halogeno-lower alkyl group, a nitrobenzyl group, a loweralkoxy-benzyl group, and benzhydryl.

The esterified hydroxy group of the formula --OA includes, for example,a di-aryl-phosphoryloxy group or a di-lower alkylphosphoryloxy group ofthe formula --OP(O)(OR⁰)₂ (wherein R⁰ is an aryl group or a lower alkylgroup), a substituted or unsubstituted lower alkylsulfonyloxyl group(e.g. methanesulfonyloxy group, ethanesulfonyloxy group,trifluoromethane-sulfonyloxy group, etc.), a substituted orunsubstituted arylsulfonyloxy group (e.g. benzenesulfonyloxy group,toluenesulfonyloxy group, etc.), a lower alkanoyloxy group (e.g. acetoxygroup, etc.), an arylcarbonyloxy group (e.g. benzoyloxy group, etc.),and the like. Among these groups, the more preferable examples areactive esterified hydroxy group such as a di-arylphosphoryloxy group, adi-lower alkylphosphoryloxy group, a substituted or unsubstituted loweralkylsulfonyloxy group, a substituted or unsubstituted arylsulfonyloxygroup, and the like.

The organic group for R⁶ in the thiol compound [X] and the1β-methylcarbapenem derivative [XI] may be any groups which are used asa substituent for the conventional carbapenem antibacterial agents, forexample, groups used for the carbapenem antibacterial agents disclosedin Japanese Patent First Publication (Kokai) Nos. 18779/1986,202886/1985, 5081/1986, 49783/1990, 279588/1992, and U.S. Pat. No.4,194,047. Examples of the organic group are a lower alkyl group, acycloalkyl group, a 6- to 8-membered aryl group, a 4- to 8-memberedaliphatic heterocyclic group, a 4- to 8-membered aromatic heterocyclicgroup, and the like. Moreover, these groups may have one or moresubstituents, and the substituent includes, for example, a lower alkylgroup, hydroxy group, a lower alkoxy group, a lower alkylamino group,mercapto group, a lower alkylthio group, amidino group, guanidino group,carbamoyl group, thiocarbamoyl group, sulfamoyl group, cyano group,carboxyl group, a lower alkoxycarbonyl group, an aralkyloxycarbonylgroup, oxo group, a halogeno group, a cycloalkyl group, a 6- to8-membered aryl group, a 4- to 8-membered aliphatic heterocyclic group,a 4- to 8-membered aromatic heterocyclic group, and the like.

The reaction of the azetidinone compound [III] and the acetic acidcompound [VII] is carried out in an appropriate solvent in the presenceof a base. The leaving group for L² in the compound [VII] includes, forexample, a halogen atom, an acyloxy group, and the like. The baseincludes, for example, an organic base such as1,8-diazabicyclo[5.4.0]undec-7-en, etc., an alkali metal compound suchas an alkali metal hydride, an alkali metal hydroxide, an alkali metalcarbonate, and an alkali metal salt of amines such as sodium amide,lithium diisopropylamide, sodium bis(trimethylsilyl)amide, and the like.The solvent includes, for example, an inert solvent such astetrahydrofuran, benzene, dichloromethane, etc. The reaction is carriedout at a temperature of -50° C. to -20° C.

The intramolecular cyclization reaction of the N-substituted azetidinonecompound [VIII] can be carried out in the presence of a base. The baseincludes, for example, an alkali metal salt of amines such as sodiumbis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, and analkali metal salt of alcohols such as potassium t-butoxide, an alkalimetal hydride such as sodium hydride, etc., and the like. The base maybe used in an amount of 1.0 to 3.0 moles, preferably 2.0 to 2.5 moles,per one mole of the compound [VIII]. The solvent includes, for example,tetrahydrofuran, ethylene glycol dimethyl ether, dioxane, toluene,diethyl ether, benzene, etc. The reaction is carried out under coolingor at room temperature, for example, at a temperature of -78° C. to 50°C., preferably at a temperature of -60° C. to 10° C.

In the above intramolecular cyclization reaction of the compound [VIII],there is presumed to obtain an intramolecular cyclization product of theformula [XII]: ##STR20## wherein R¹, R⁴ and R⁵ are the same as definedabove.

The compound [XII] thus obtained may be isolated from the reactionmixture or subjected to the subsequent esterification reaction withoutisolation. However, the intramolecular cyclization reaction and thesubsequent esterification reaction may be preferably carried out in thesame solvent without isolation of the compound [XII].

The esterification reaction of the compound [XII] can be carried out byreacting it with an esterifying reagent for hydroxy group. Examples ofthe esterifying reagent for hydroxy group are a reactive derivative(e.g. a corresponding acid halide, a corresponding acid anhydride) ofphophoric acid compound or sulfuric acid compound such as a di-arylphosphate (e.g. diphenyl phosphate, etc.), a di-lower alkyl phosphate(e.g. diethyl phosphate, etc.), a substituted or unsubstituted loweralkanesulfonic acid (e.g. methane-sulfonic acid, ethanesulfonic acid,trifluoromethanesulfonic acid, etc.), a substituted or unsubstitutedarylsulfonic acid (e.g. benzenesulfonic acid, toluenesulfonic acid,etc.), or a reactive derivative (e.g. a corresponding acid halide, acorresponding acid anhydride) of a lower alkanoic acid (e.g. aceticacid, etc.) or an arylcarboxylic acid (e.g. benzoic acid, etc.). Theesterifying reagent for hydroxy group may be used in an amount of 1.0 to4.0 moles, preferably 2.0 to 3.0 moles, per one mole of the compound[VIII].

Among them, the preferred esterifying reagents for hydroxy group arepreferably an active esterifying reagent for hydroxy group such as areactive derivative (e.g. a corresponding acid halide, a correspondingacid anhydride) of phosphoric acid compound or sulfuric acid compound,for example, a reactive derivative (e.g. a corresponding acid halide, acorresponding acid anhydride) of a di-aryl phosphate, a di-lower alkylphosphate, a substituted or unsubstituted lower alkanesulfuric acid, asubstituted or unsubstituted arylsulfonic acid. The reaction is carriedout under cooling or at room temperature, preferably at a temperature of-75° C. to 40° C., more preferably at a temperature of -60° C. to 10° C.

The intramolecular cyclization reaction of the compound [VIII] and thesubsequent esterification reaction are carried out in the presence orabsence of an acid, but it is preferable to carry out these reactions inthe presence of an acid.

The acid may be either a Lewis acid or protonic acid, but Lewis acidsare more preferable. The Lewis acid includes, for example, a metalhalide such as cupric chloride, cuprous iodide, zinc chloride, zinciodide, zinc fluoride, ferric chloride, stannous chloride, stannicchloride, etc., and boron compounds such as trimethyl borate, etc., or asilyl compound such as tri-lower alkyl-halogenosilane (e.g.trimethylchlorosilane, t-butyldimethylchlorosilane, etc.), atetrahalogenosilane (e.g. tetrachlorosilane, etc.). The Lewis acid maybe used in an amount of 0.1 to 2.0 moles, preferably 1.0 to 1.5 moles,per one mole of the compound [VIII].

The protonic acid includes, for example, sulfuric acid,β-toluene-sulfonic acid, acetic acid, citric acid, hydrochloric acid,phosphoric acid, boric acid, etc., and may be used in an amount of 0.1to 1.0 mole per one mole of the compound [VIII].

When the above esterification reaction is carried out in the presence ofan acid, the esterifying reagent may be used in an amount of 1.2 to 1.5moles per one mole of the compound [VIII].

The reaction of the 1β-methyl-2-oxycarbapenem derivative [IX] and thethiol compound [X] is carried out according to the method disclosed inJapanese Patent First Publication (Kokai) No. 279588/1992. When R⁴ is aprotected hydroxy-substituted lower alkyl group, and/or R⁵ is an esterresidue, the protecting group for said hydroxy group and/or the esterresidue may be removed by a conventional method, for example,hydrolysis, reduction, etc., if necessary.

In the above reactions, the compounds [VIII], [IX] and [X] may be usedin the form of a salt thereof as well. The salts of these compounds[VIII], [IX] and [X] are, for example, an alkali metal salt, a tri-loweralkylammonium salt, etc.

Since the present process proceeds with keeping the stereo-structure ofthe compound [III], the compound [III] can be converted into the1β-methyl-2-oxycarbapenem derivative [IX] and the 1β-methylcarbapenumderivative [XI] without epimerization.

Besides, the compound [IV] can be prepared by a conventional method.Among them, the benzene compound of the formula[IV-2]: ##STR21## whereinY² is oxygen atom, sulfur atom or an imino group which may havesubstituent(s), and Ring B, X, Z¹ and Z² are the same as defined above,is prepared by the method disclosed in journal of the American ChemicalSociety, 72, 721 (1950). That is, the compound [IV-2] is prepared bycondensing a compound of the formula [XIII]: ##STR22## wherein Ring B, Xand Y² are the same as defined above, with a compound of the formula[XIV]: ##STR23## wherein Z¹ and Z² are the same as defined above, in thepresence of an acid (e.g. p-toluenesulfonic acid, sulfuric acid,hydrochloric acid, etc.).

Besides, the compound [XIII] in which X is oxygen atom and Y² is sulfuratom may be prepared by halogenating a compound of the formula [XV]:##STR24## wherein Ring B is the same as defined above, to give acompound of the formula [XVI]: ##STR25## wherein X² is a halogen atom,and Ring B is the same as defined above, subjecting the compound [XVI]to amidation to give a compound of the formula [XVll]: ##STR26## whereinRing B is the same as defined above, and then reducing the compound[XVII].

Besides, the compound [XIII] in which X is oxygen atom and Y² is animino group which may have substituents(s) may be prepared by reacting acompound of the formula [XVIII]: ##STR27## wherein Y₃ is an imino groupwhich may have substituent(s), and other symbols are the same as definedabove, with ammonia.

Besides, the compound [XIII] in which X is sulfur atom and Y² is sulfuratom or an imino group which may have substituent(s) may be prepared bysubjecting the compound [XIII] in which X is oxygen atom and Y₂ issulfur atom or an imino group which may have substituent(s) tothiocarbonylation.

Besides, the benzene compound [IV-1] in which Y is methylene group maybe prepared by reacting the compound of the formula: ##STR28## whereinL³ is a halogen atom or hydroxy group, and Ring B is the same as definedabove, with a compound of the formula: ##STR29## wherein Z¹ and Z² arethe same as defined above, to give a compound of the formula: ##STR30##wherein the symbols are the same as defined above, reducing the compoundto give a compound of the formula: ##STR31## wherein the symbols are thesame as defined above, reacting the compound with a compound of theformula: ##STR32## wherein X is the same as defined above, and thensubjecting the product to intramolecular cyclization.

Throughout the present specification and claims, the lower alkyl group,the lower alkylene group and the lower alkoxy group are preferably astraight chain or branched chain alkyl group, alkoxy group and alkylenegroup having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms,respectively. The lower alkanoyl group and the lower alkenyl group areones having 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms,respectively. The lower alkenoyl group and the cycloalkyl group are oneshaving 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms,respectively.

EXAMPLES

The present invention is illustrated in more detail by the followingExamples and Reference Example, but should not be construed to belimited thereto.

Example 1

To a solution of 2,2-di-n-butyl-2,3-dihydro-4H-1,3-benzoxadin-4-one(13.5 g, 51.7 mmole) in methylene chloride (30 ml) are added dropwise asolution of propionyl bromide (6.05 ml, 67.2 mmole) in methylenechloride (15 ml) and a solution of pyridine (5.02 ml, 62.0 mmole) inmethylene chloride (15 ml) at -20° C. under nitrogen atmosphere over aperiod of about 30 minutes. After the addition, the reaction mixture iswarmed gradually, and stirred at room temperature overnight. To thereaction mixture is added water (50 ml), and the mixture is separated.The aqueous layer is extracted with methylene chloride (50 ml), and theorganic layers are combined, and washed successively with saturatedsodium hydrogen carbonate solution and saturated saline solution, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue is purified by silica gel column chromatography(solvent; hexane/ethyl acetate=19:1) to give2,2-di-n-butyl-3-propionyl-2,3 -dihydro-4H-1,3-benzoxadin-4-one (14.8g).

Yield; 90%

M.p. 52°-54° C.

NMR δ (CDCl₃): 0.65 (6H, t, J=5.0 Hz), 1.03-1.62 (11H, m), 1.94-2.44(4H, m), 2.91 (2H, q, J=7.2 Hz), 6.91 (1H, d, J=8.0 Hz), 7.07 (1H, dd,J=7.8, 7.8 Hz), 7.50 (1H, ddd, J=1.6, 8.0, 8.0 Hz), 7.94 (1H, dd, J=1.6,8.0 Hz),

IR (KBr) cm-⁻¹ : 1718, 1682, 1610, 1469, 1174

Example 2

Using solutions ofspiro[2,3-dihydro-4H-1,3-benzoxadine-2,1'-cyclohexan]-4-one (30.0 g, 138mmole) in methylene chloride (60 ml), propionyl bromide (16.1 ml, 179mmole) in methylene chloride (30 ml) and pyridine (13.4 ml, 166 mmole)in methylene chloride (30 ml),3-propionyl-spiro[2,3-dihydro-4H-1,3-benzoxadine-2,1'-cyclohexan]-4-one(34.7 g) is obtained in the same manner as in Example 1.

Yield; 92%

M.p. 58°-60° C.

NMR δ (CDCl₃): 1.20 (3H, t, J=7.4 Hz), 1.16-1.43 (2H, m), 1.55-1.81 (4H,m), 1.98-2.40 (4H, m), 2.84 (2H, q, J=7.4 Hz), 6.98 (1H, d, J=8.2 Hz),7.10 (1H, dd, J=7.6, 7.6 Hz), 7.52 (1H, ddd, J=1.6, 7.6, 7.6 Hz), 7.95(1H, dd, J=1.6, 8.2 Hz)

IR (KBr)cm⁻¹ : 1724, 1687, 1611, 1467, 1320, 1159

Example 3

To a solution of2,2-di-n-butyl-3-propionyl-2,3-dihydro-4H-1,3-benzoxadin-4-one (190 mg,0.6 mmole) in tetrahydrofurn (3 ml) is added dropwise 1M solution (0.7ml) of sodium bis(trimethylsilyl)amide in tetrahydrofuran at -60° C.under nitrogen atmosphere, and the mixture is stirred at the sametemperature for one hour. To the mixture is added dropwise(3R,4R)-4-acetoxy-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-azetidinone(143 mg, 0.5 mmole) in tetrahydrofuran (1 ml) at -50° C., and themixture is stirred for 10 minutes. To the reaction solution is added0.1M phosphate buffer (pH 7.0, 10 ml), and the mixture is extracted withethyl acetate (10 ml). The buffer layer is extracted with ethyl acetate(5 ml), and the organic layers are combined, washed with water, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue is purified by silica gel column chromatography(solvent; hexane/ethyl acetate=20:1 to 4:1) to give 3-{(2R)-2-[(3S, 4R)-3-[(1R)-1-t-butylkimethyisilyloxyethyl]-2-oxazetidin-4-yl]-propionyl-2,2-di-n-butyl-2,3-dihydro-4H-1,3-benzoxadin-4-one(237 mg).

Yield; 87%

M.p. 100°-102° C.

β:α=100:0 (HPLC)

NMR δ (CDCl₃): 0.07 (9H, s), 0.78-1.02 (12H, m), 1.10-1.58 (11H, m),1.92-2.44 (4H, m), 3.13-3.20 (1H, m), 3.70-3.82 (1H, m), 4.07-4.24 (2H,m) 5.97 (1H), s), 6.92 (1H, d, J=8.1 Hz), 7.09 (1H, dd, J=7.4, 7.4 Hz),7.53 (1H, ddd, J=1.6, 8.1, 8.1 Hz), 7.93 (1H, dd, J=1.6, 7.4 Hz)

Example 4

3-Propionyl-spiro[2,3-dihydro-4H-1,3-benzoxadine-2,1'-cyclohexan]-4-one(164 mg, 0.6 mmole) is reacted with(3R,4R)-4-acetoxy-3-[(1R)-1-t-butyldimethylsilyloxyethyl[-2-azetidinone(143 mg, 0.5 mmole) in the same manner as Example 3 to give3-{(2R)-2-[(3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro[2,3-dihydro-4H-1,3-benzoxadin-2,1'-cyclohexan]-4-one(205 mg).

Yield; 82%

M.p. 149°-151° C.

β:α=100:0 (HPLC)

NMR δ (CDCl₃): 0.07 (9H, s), 0.85 (6H, s), 1.16-1.40 (5H, m), 1.50-2.40(8H, m), 3.16-3.24 (1H, m), 3.48-3.63 (1H, m), 4.00-4.30 (2H, m), 5.95(1H, s), 7.00 (1H, d, J=8.2 Hz), 7.11 (1H, dd, J=7.5, 7.5 Hz), 7.54 (1H,ddd, J=1.6, 7.5, 7.5 Hz), 7.93 (1H, dd, J=1.6, 8.2 Hz)

Example 5

Using lithium bis(trimethylsilyl)amide instead of sodiumbis(trimethylsilyl)amide,3-{(2R)-2-[(3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-2,2-di-n-butyl-2,3-dihydro-4H-1,3-benzoxadin-4-oneis obtained is obtained in the same manner as in Example 3.

β:α=100:0 (HPLC)

Example 6

Using lithium bis(trimethylsilyl)amide,3-{(2R)-2-[(3S,4R)-3-[(1R)-1-t-butyldimethylsilyoxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro[2,3-dihydro-4H-1,3-benzoxadin-2,1'-cyclohexan]-4-one is obtained in the same manner asin Example 4.

β:α=100:0 (HPLC)

Examples 7 to 18

The corresponding starting compounds and propionyl chloride are treatedin the same manner as in Example 1 to give the compounds listed in Table1.

                  TABLE 1                                                         ______________________________________                                         ##STR33##                                                                    Ex.                                                                           No.   X     Y         Z.sup.1 Z.sup.2 M.p. (°C.)                       ______________________________________                                         7    O     O         CH.sub.3                                                                              CH.sub.3                                                                              26-27                                    8    O     O         C.sub.2 H.sub.5                                                                       C.sub.2 H.sub.5                                                                       47-49                                    9    O     O         C.sub.15 H.sub.31                                                                     C.sub.15 H.sub.31                                                                     68-71                                   10    O     O         PhCH.sub.2                                                                            PhCH.sub.2                                                                            76-77                                   11    S     O         (CH.sub.2).sub.5                                                                            102-104                                   12    S     O         CH.sub.3                                                                              CH.sub.3                                                                              46-48                                   13    O     S         (CH.sub.2).sub.5                                                                            101-102                                   14    O     CH.sub.2  H       H       82-83                                   15    O     NCH.sub.3 CH.sub.3                                                                              CH.sub.3                                                                              58-60                                   16    O     O         (CH.sub.3).sub.2 CH                                                                   (CH.sub.3).sub.2 CH                                                                   Oil*                                    17    O     O         C.sub.3 H.sub.7                                                                       C.sub.3 H.sub.7                                                                       41-42                                   18    O     O         C.sub.6 H.sub.5                                                                       C.sub.6 H.sub.5                                                                       197-200                                 ______________________________________                                         *B.p. 145-150° C. (1-2 mmHg)                                      

Examples 19 to 46

The corresponding starting compounds and propionyl bromide are treatedin the same manner as in Example 1 to give the compounds listed inTables 2 and 3.

                  TABLE 2                                                         ______________________________________                                         ##STR34##                                                                    Ex.                                                                           No.  X     Y        Z.sup.1                                                                              Z.sup.2                                                                             Ring B                                       ______________________________________                                        19   O     O        CH.sub.3                                                                             CH.sub.3                                                                             ##STR35##                                   20   O     O        C.sub.15 H.sub.31                                                                    C.sub.15 H.sub.31                                                                    ##STR36##                                   21   O     O        PhCH.sub.2                                                                           PhCH.sub.2                                                                           ##STR37##                                   22   O     O        (CH.sub.2).sub.4                                                                          ##STR38##                                     23   O     S        C.sub.4 H.sub.9                                                                      C.sub.4 H.sub.9                                                                      ##STR39##                                   24   O     NCH.sub.3                                                                              (CH.sub.2).sub.5                                                                          ##STR40##                                     25   S     O        C.sub.4 H.sub.9                                                                      C.sub.4 H.sub.9                                                                      ##STR41##                                   26   S     S        (CH.sub.2).sub.5                                                                          ##STR42##                                     27   S     NCH.sub.3                                                                              PhCH.sub.2                                                                           PhCH.sub.2                                                                           ##STR43##                                   28   O     CH.sub.2 CH.sub.3                                                                             CH.sub.3                                                                             ##STR44##                                   29   O     O        (CH.sub.2).sub.5                                                                          ##STR45##                                     30   O     O        (CH.sub.2).sub.5                                                                          ##STR46##                                     31   O     O        (CH.sub.2).sub.5                                                                          ##STR47##                                     32   S     S        CH.sub.3                                                                             CH.sub.3                                                                             ##STR48##                                   33   S     S        (CH.sub.2).sub.4                                                                          ##STR49##                                     34   O     NCH.sub.3                                                                              C.sub.4 H.sub.9                                                                      C.sub.4 H.sub.9                                                                      ##STR50##                                   35   O     CH.sub.2 (CH.sub.2).sub.5                                                                          ##STR51##                                     36   O     O        (CH.sub.2).sub.4                                                                          ##STR52##                                     37   O     S        C.sub.4 H.sub.9                                                                      C.sub.4 H.sub.9                                                                      ##STR53##                                   38   S     O        C.sub.4 H.sub.9                                                                      C.sub.4 H.sub.9                                                                      ##STR54##                                   ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                         ##STR55##                                                                    Ex. No.   X.sup.1                                                                             Y.sup.1     R.sup.12                                                                              R.sup.22                                  ______________________________________                                        39        O     O           (CH.sub.3).sub.2 CH                                                                   H                                         40        S     O           (CH.sub.3).sub.2 CH                                                                   H                                         41        O     S           CH.sub.3                                                                              CH.sub.3                                  42        S     S           (CH.sub.3).sub.2 CH                                                                   H                                         43        O     NCH.sub.3   CH.sub.3                                                                              CH.sub.3                                  44        O     O           CH.sub.3                                                                              CH.sub.3                                  45        S     S           CH.sub.3                                                                              CH.sub.3                                  46        O     O           (CH.sub.3).sub.2 CH                                                                   H                                         ______________________________________                                    

Examples 47 to 66

The corresponding starting compounds and (3R,4R)-4-acetoxy-3-(1R)-1-t-butyldimethylsilyloxyethyl]-2-azetidinone are treated in thesame manner as in Example 3 to give the compounds listed in Tables 4 and5.

                                      TABLE 4                                     __________________________________________________________________________     ##STR56##                                                                    Ex.                                                                           No.                                                                              X Y   Z.sup.1                                                                             Z.sup.2                                                                             M.p. (°C.)                                                                   β/α                                                                    Ring B                                         __________________________________________________________________________    47 O O   CH.sub.3                                                                            CH.sub.3                                                                            131-133                                                                              99/1                                                                              ##STR57##                                     48 O O   C.sub.15 H.sub.31                                                                   C.sub.15 H.sub.31                                                                   Oil    99/1                                                                              ##STR58##                                     49 O O   PhCH.sub.2                                                                          PhCH.sub.2                                                                          Caramel                                                                                  ##STR59##                                     50 O O   C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                     181-183                                                                             100/0                                                                              ##STR60##                                     51 S O   (CH.sub.2).sub.5                                                                          143-144                                                                             100/0                                                                              ##STR61##                                     52 S O   CH.sub.3                                                                            CH.sub.3                                                                            146-148                                                                             100/0                                                                              ##STR62##                                     53 O S   (CH.sub.2).sub.5                                                                          147-150                                                                              96/4                                                                              ##STR63##                                     54 O CH.sub.2                                                                          H     H     143-146                                                                              93/7                                                                              ##STR64##                                     55 O NCH.sub.3                                                                         CH.sub.3                                                                            CH.sub.3                                                                            141-144                                                                                  ##STR65##                                     56 O O   (CH.sub.3).sub.2 CH                                                                 (CH.sub.3).sub.2 CH                                                                 119-120                                                                             100/0                                                                              ##STR66##                                     57 O O   C.sub.3 H.sub.7                                                                     C.sub.3 H.sub.7                                                                     185-187                                                                             100/0                                                                              ##STR67##                                     58 O O   C.sub.6 H.sub.5                                                                     C.sub.6 H.sub.5                                                                     Syrup  94/6                                                                              ##STR68##                                     59 O CH.sub.2                                                                          CH.sub.3                                                                            CH.sub.3                                                                            Syrup                                                                                    ##STR69##                                     60 O O   (CH.sub.2).sub.5                                                                          Syrup                                                                                    ##STR70##                                     61 O O   (CH.sub.2).sub.5                                                                          173-175                                                                                  ##STR71##                                     62 O O   (CH.sub.2).sub.5                                                                          155-158                                                                                  ##STR72##                                     __________________________________________________________________________     TBS: tButyldimethylsilyl group                                           

                  TABLE 5                                                         ______________________________________                                         ##STR73##                                                                    Ex.                                                                           No.  X.sup.1                                                                             Y.sup.1                                                                              R.sup.12                                                                              R.sup.22                                                                            IRν.sub.max (cm.sup.-1)                                                              β/α                      ______________________________________                                        63   O     O      (CH.sub.3).sub.2 CH                                                                   H     1697, 1778, 3330                                                                        100/0                               64*  O     O      CH.sub.3                                                                              CH.sub.3                                                                            1706, 1762, 3200                                                                        70/30                               65*  S     S      CH.sub.3                                                                              CH.sub.3                                                                            1772, 1761, 3180                              66*  O     O      (CH.sub.3).sub.2 CH                                                                   H               100/0                               ______________________________________                                         TBS: tButyldimethylsilyl group                                                *Lithium bis(trimethylsilyl)amide is used instead of sodium                   bis(trimethylsilyl)amide.                                                

Examples 67 to 80

The corresponding starting compounds and(3R,4R)-4-acetoxy-3-(1R)-1-t-butyldimethylsilyloxyethyl]-2-azetidinoneare treated in the same manner as in Example 3 to give the compoundslisted in Tables 6 and 7.

                  TABLE 6                                                         ______________________________________                                         ##STR74##                                                                    Ex. No.    X     Y           Z.sup.1 Z.sup.2                                  ______________________________________                                        67         O     O           (CH.sub.2).sub.4                                 68         O     S           C.sub.4 H.sub.9                                                                       C.sub.4 H.sub.9                          69         O     NCH.sub.3   (CH.sub.2).sub.5                                 70         S     O           C.sub.4 H.sub.9                                                                       C.sub.4 H.sub.9                          71         S     S           (CH.sub.2).sub.5                                 72         S     NCH.sub.3   PhCH.sub.2                                                                            PhCH.sub.2                               73         S     S           CH.sub.3                                                                              CH.sub.3                                 74         S     S           (CH.sub.2).sub.4                                 75         O     NCH.sub.3   n-C.sub.4 H.sub.9                                                                     n-C.sub.4 H.sub.9                        76         O     CH.sub.2    (CH.sub.2).sub.5                                 ______________________________________                                         TBS: tButyldimethylsilyl group                                           

                  TABLE 7                                                         ______________________________________                                         ##STR75##                                                                    Ex. No.    X.sup.1                                                                             Y.sup.1    R.sup.12                                                                              R.sup.22                                  ______________________________________                                        77         S     O          (CH.sub.3).sub.2 CH                                                                   H                                         78         O     S          CH.sub.3                                                                              CH.sub.3                                  79         S     S          (CH.sub.3).sub.2 CH                                                                   H                                         80         O     NCH.sub.3  CH.sub.3                                                                              CH.sub.3                                  ______________________________________                                         TBS: tButyldimethylsilyl group                                           

Example 81

Using sodium methylate, 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-2,2-di-n-butyl-2,3-dihydro-4H-1,3-benzoxadin-4-oneis obtained in the same manner as in Example 3.

Example 82

(A) To a solution of3-{(2R)-2-[(3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro[2,3-dihydro-4H-1,3-benzoxadine-2,1'-cyclohexan]-4-one(7 g) and bromoacetic acid allyl ester (2.89 g) in tetrahydrofuran (35ml) is added 1M sodium bis(trimethylsilyl)amido•tetrahydrofuran solution(16.2 ml) at -60° C., and the mixture is warmed to -30° C. over onehour. The reaction solution is poured into a mixture of water-ethylacetate, and the ethyl acetate layer is washed, dried, and evaporated toremove the solvent. The residue is purified by silica gel columnchromatography (solvent; hexane/ethyl acetate =20:1 to 5:1) to give3-{(2R)-2-[(3S,4R)-1-allyloxycarbonylmethyl-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro[2,3-dihydro-4H-1,3-benzoxadine-2,1'-cyclohexan]-4-one(8.03 g) as syrup.

(B) A solution of3-{(2R)-2-[(3S,4R)-1-allyloxycarbonylmethyl-3-[(1R)-1-t-butyldimethylsilyloxyoxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro[2,3-dihydro-4H-1,3-benzoxadine-2,1'-cyclohexan]-4-one(1.2 g) in tetrahydrofuran (6 ml) is added dropwise to 1M sodiumbis(trimethylsilyl)amide•tetrahydrofuran solution (4.4 ml) at atemperature of -30° C. to -20° C. over one minute. To the mixture isadded trimethylsilyl chloride (261 mg) at -50° C., and the mixture isstirred for two minutes. To the mixture is added diphenylphosphorylchloride (645 mg) at -50° C., and the mixture is stirred at 0° C. fortwo hours. The reaction solution is poured into 0.2M phosphate buffer(pH 7.0, 50 ml), and the mixture is extracted with ethyl acetate. Theextract is washed, dried, and evaporated to remove the solvent. To theresidue is added isopropyl ether, and the mixture is filtered to collectspiro[2,3-dihydro-4H-1,3-benzoxadin-2,1'-cyclohexan]-4-one (355 mg) asprecipitates. The flitrate is concentrated to give(1R,5R,6S)-6-[(1R)-1-t-butyldimethylsilyloxyethyl]-1-methyl-2-diphenylphosphoryloxy-carbapen-2-em-3-carboxylicacid allyl ester (1.04 g) as syrup.

Example 83

To a solution of3-{(2R)-2-[(3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro[2,3-dihydro-4H-1,3-benzoxadin-2,1'-cyclohexan]-4-one(500 mg) in tetrahydrofuran/water (20 ml) are added successively 30%aqueous hydrogen peroxide solution (0.9 ml) and lithium hydroxide (84mg) at 0° C., and the mixture is stirred at the same temperature for onehour. To the mixture is added dropwise 1.5N aqueous sodium sulfitesolution (5 ml) at the same temperature to adjust the pH value of themixture to about pH 10. The mixture is evaporated under reduced pressureto remove the tetrahydrofuran. The precipitated crystals are removed byfiltration, and the aqueous flitrate is washed with chloroform (20 ml),and thereto is added 10% hydrochloric acid (10 ml) to adjust the pHvalue of the mixture to about pH 1. The aqueous layer is extracted withethyl acetate (30 ml), and the organic layer is dried, concentratedunder reduced pressure, and recrystallized from a mixture of ethylacetate/hexane to give(2R)-2-[(3S,4R)-3-[(1R)-1-t-butyl-dimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionicacid (216 mg).

M.p. 146°-147° C.

Reference Example 1

Dibutyl ketone (20 g), salicylamide (19.3 g) and β-toluenesulfonic acidhydrate (2.7 g) are added to toluene (300 ml), and the mixture isrefluxed overnight during which the water is removed by Dean-Starkapparatus. After cooling, the reaction solution is washed, dried, andevaporated to remove the solvent. The residue is purified by silica gelcolumn chromatography (solvent; hexane/ethyl acetate=95:5) to give2,2-dibutyl-4-oxo-2,3-dihydro-4H-1,3-benzoxadine (34 g) as yellow oil.

Reference Example 2

(1) Thionyl chloride (12.5 ml) is added dropwise to a solution of2,2'-dithiodibenzoic acid (25.0 g) in a mixture of toluene (120 ml) anddimethyl-formamide (0.5 ml) at room temperature. The mixture is warmedto a temperature of 70° to 80° C. and then stirred at the sametemperature overnight. After 20 hours, the crystals are collected byfiltration to give 2,2'-dithiodibenzoyl chloride (14.9 g) as colorlesscrystal.

M.p. 140°-141° C.

(2) Aqueous ammonia (20 ml) is added to a suspension of2,2'-dithiodibenzoyl chloride (7.03 g) in dioxane (20 ml) at roomtemperature. The mixture is warmed to a temperature of 80° to 90° C. andstirred for five hours at the same temperature. The mixture is cooled toroom temperature to give 2,2'-dithiodibenzoylamide (4.8 g) as colorlesscrystal.

M.p. 249°-250° C.

(3) 2N Hydrochloric acid (41 ml) is added dropwise to a suspension of2,2'-dithiodibenzoylamide (4.14 g) and zinc powders (2.5 g) in dioxane(70 ml). The mixture is warmed to a temperature of 60° to 70° C. andstirred for four hours at the same temperature. The reaction mixture ispoured into water (50 ml), and the mixture is extracted with ethylacetate. The ethyl acetate layer is washed, dried and evaporated underreduced pressure to remove the solvent. A mixture of cyclohexanone (5.64ml) and p-toluenesulfonic acid monohydrate (1.03 g) is added to asolution of the above obtained residue in toluene, and the mixture isrefluxed for 40 minutes by making use of a dehydrator of Dean Stark.After cooling to room temperature, the reaction mixture is condensedunder reduced pressure and methanol is added thereto. The precipitatesare collected by filtration to givespiro[2,3-dihydro-4H-1,3-benzothiazine-2,1'-cyclohexan]-4-one (3.05 g)as colorless crystal.

M.p. 193°-195° C.

Reference Example 3

(1) N-Methylisatic acid (10.0 g) is added gradually to water (140 ml) atroom temperature and thereto is added dropwise aqueous ammonia (9.6 g).The mixture is warmed to 80° C. during 45 minutes, and ethanol is addedthereto until the reaction mixture becomes colorless. Then, the reactionmixture is cooled to room temperature and the precipitated crystals arecollected by filtration to give 2-carbamoyl-N-methylaniline (7.11 g) ascolorless crystal.

M.p. 155°-156° C.

(2) A mixture of cyclohexanone (6.9 ml) and p-toluenesulfonic acidmonohydrate (633 mg) is added to a solution of the above obtainedproduct (5.00 g) in toluene, and the mixture is refluxed withdehydration by making use of a dehydrator of Dean Stark for one hour.After cooling to room temperature, the precipitated crystals arecollected by filtration and washed with methanol to givespiro[1-methyl-1,2,3,4-tetrahydroquinazoline-2,1'-cyclohexan]-4-one(6.32 g) as colorless crystal.

M.p. 183°-185° C.

Reference Example 4

(1) A solution of ethoxycarbonyl chloride (9.6 g) in ether (25 ml) isadded dropwise to a solution of1-(2-amino-2-methylpropyl)-4-methoxybenzene (30 g) in ether (300 ml)under ice-cooling. Then, a solution of ethoxycarbonyl chloride (9.6 g)in ether (25 ml) and a solution of sodium hydroxide (8 g) in water (50ml) are added dropwise thereto. After addition, the mixture is stirredfor one hour, and water is added thereto. The ether layer is removedtherefrom and the aqueous layer is extracted with ether twice. A mixtureof the ether layer and the extract is dried and evaporated to remove thesolvent. The residue is purified by column chromatography to give1-[2-(N-ethoxycarbonyl)amino-2-methylpropyl]-4-methoxybenzene (29.1 g)as an oil.

NMR (CDCl₃) δ1.02 (6H, s), 1.32 (3H, t, J=7.5 Hz), 3.12 (2H, s), 3.72(3H, s), 4.17 (2H, q, J=7.5 Hz), 6.70-7.10 (4H, m)

(2) The above product (10 g) is added to polyphosphoric acid (100 ml)and the mixture is stirred at room temperature for 30 minutes. Then, themixture is gradually warmed to a temperature of 100° C. and stirred atthe same temperature for two hours. After cooling to room temperature,water (300 ml) is added thereto and the mixture is extracted withchloroform. The extract is dried and evaporated to remove the solvent.The residue is purified by column chromatography to give1-oxo-3,3-dimethyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline (5.43 g) asan oil.

NMR (CDCl₃) δ1.02 (6H, s), 3.10 (2H, s), 3.72 (3H, s), 6.90 (1H, d, J=9Hz), 7.45 (1H, dd, J=3 Hz, 9 Hz), 7.85 (1H, d, J=3 Hz)

Reference Examples 5 to 14

The corresponding starting compounds [XII] and the correspondingstarting compounds [XIV] are treated in the same manner as in ReferenceExample 1 to give the compounds listed in Table 8.

                                      TABLE 8                                     __________________________________________________________________________     ##STR76##                                                                    Ref.                                                                          Ex. No.                                                                            Z.sup.1   Z.sup.2   Ring B     Y   M.p. (°C.)                     __________________________________________________________________________     5   n-C.sub.15 H.sub.31                                                                     n-C.sub.15 H.sub.31                                                                      ##STR77## O   Yellow Oil                             6                                                                                  ##STR78##                                                                               ##STR79##                                                                               ##STR80## O   159-161                                7   (CH.sub.2).sub.5                                                                                   ##STR81## O   168-170                                8   (CH.sub.2).sub.5                                                                                   ##STR82## O   175-177                                9   (CH.sub.2).sub.5                                                                                   ##STR83## O   193-195                               10   (CH.sub.3).sub.2 CH                                                                     (CH.sub.3).sub.2 CH                                                                      ##STR84## O   117-119                               11   n-C.sub.3 H.sub.7                                                                       n-C.sub.3 H.sub.7                                                                        ##STR85## O   61-63                                 12                                                                                  ##STR86##                                                                               ##STR87##                                                                               ##STR88## O   240-245                               13   n-C.sub.4 H.sub.9                                                                       n-C.sub.4 H.sub.9                                                                        ##STR89## NCH.sub.3                                                                         77-78                                 14   CH.sub.3  CH.sub.3                                                                                 ##STR90## NCH.sub.3                                                                         156-158                               __________________________________________________________________________

Effects of the Invention

According to the present invention, the azetidinone compound [III],which is useful as a synthetic intermediate for carbapenem derivatives,is prepared by reacting the alkanamide compound [I] with the compound[II] in the presence of a base without using a Lewis acid.

Especially, when the compound [I] wherein the group of the formula--N(R²)(R³) is a group of the formula: ##STR91## wherein Ring B, X, Y,Z¹ and Z² are the same as defined, and R¹ is a lower alkyl group,especially methyl group, is used in the present process, there isstereoselectively obtained the compound of the formula [Ill-A]:##STR92## wherein R¹⁵ is a lower alkyl group and R⁴, Ring B, X, Y, Z¹and Z² are the same as defined above, having R¹ with β-configuration.Therefore, the present invention can provide a synthetic intermediateuseful for 1β-methylcarbapenem derivative having an antibacterialactivity.

Besides, the compound [Ill-A] can be converted into the compound [XII]and the compound [IX] without activating the 4-side chain of thecompound [III-A] by chemical modification, and during the reaction fromthe compound [III-A] to the compound [XII] and the compound [IX], thegroup of the formula: ##STR93## wherein Ring B, X, Y, Z¹ and Z² are thesame as defined above, can easily be removed and can be recovered as thecompound [IV] after the reaction, and hence, the process for preparingthe compound [IX] using the compound [Ill-A] is extremely excellentprocess from practical and economical points.

Moreover, the novel alkanamide compound [I-A] can easily be prepared,and in particularly, the compound [I-A] wherein both X and Y are oxygenatom and Ring B is unsubstituted benzene ring is industrially excellentreagent because it can be prepared from a commercially availablesalicylamide by two steps.

Thus, according to the present process, the azetidinone compound [III],the azetidinonepropionic acid [VI] and the 1β-methylcarbapenemderivative [XI] can be industrially and advantageously prepared at lowcost because it is not necessary to perform the optical resolution, touse the expensive Lewis acid, to treat the waste fluid especially, touse the alkylation method, which is difficult to be industrially carriedout.

What is claimed is:
 1. A process for preparing an azetidinone compoundof the formula (III): ##STR94## wherein R¹ is a lower alkyl group,R² andR³ combine together with the adjacent nitrogen atom to form aheterocyclic group which is a member selected from the group consistingofa group of the formula: ##STR95## wherein X¹ is an oxygen atom or asulfur atom, Y¹ is an oxygen atom, a sulfur atom, a methylene group oran imino group substituted by an alkyl group or an aryl group, and R¹¹,R¹², R¹³ and R¹⁴ are the same or different and each a hydrogen atom, aC₁ -C₅ alkyl group, a cyano group, an alkoxycarbonyl group, an aralkylgroup, or an aryl group, or R¹¹ and R¹² combine together to form a C₂-C₆ alkylene chain, and, simultaneously or independently, R¹³ and R¹⁴combine together to form a C₂ -C₆ alkylene chain, or R¹¹, R¹², R¹³ andR¹⁴ combine together with the adjacent two carbon atoms to form asubstituted or unsubstituted aromatic cyclic group, a group of theformula: ##STR96## wherein X is an oxygen atom or a sulfur atom, Y is anoxygen atom, a sulfur atom, a protected or unprotected imino group or amethylene group, Z¹ and Z² are the same or different and each a hydrogenatom, a substituted or unsubstituted alkyl group, a substituted orunsubstituted cycloalkyl group, an aryl group or an aralkyl group, orboth combine at the end thereof to form a substituted or unsubstitutedalkylene group having 4 to 7 carbon atoms, and Ring A is a substitutedor unsubstituted benzene ring or a substituted or unsubstitutedheterocyclic ring having 1 to 4 hetero atoms selected from an oxygenatom, a sulfur atom and a nitrogen atom, and a group of the formula:##STR97## wherein X, Y and Ring A are the same as defined above, and R⁴is a protected or unprotected hydroxy-substituted lower alkyl group,which comprises reacting an alkanamide compound of the formula (I):##STR98## wherein R¹, R² and R³ are the same as defined above, with acompound of the formula (II): ##STR99## wherein L¹ is a leaving groupand R⁴ is the same as defined above, in the presence of a base withoutusing a Lewis acid.
 2. A process for preparing an azetidinone alkanoicacid compound of the formula (VI): ##STR100## wherein R¹ is a loweralkyl group and R⁴ is a protected or unprotected hydroxy-substitutedlower alkyl group, which comprises reacting an alkanamide of the formula(I): ##STR101## wherein R¹ is the same as defined above, and R² and R³combine together with the adjacent nitrogen atom to form a heterocyclicgroup which is a member selected from the group consisting ofa group ofthe formula: ##STR102## wherein X¹ is an oxygen atom or a sulfur atom,Y¹ is an oxygen atom, a sulfur atom, a methylene group or an imino groupsubstituted by an alkyl group or an aryl group, and R¹¹, R¹², R¹³ andR¹⁴ are the same or different and each a hydrogen atom, a C₁ -C₅ alkylgroup, a cyano group, an alkoxycarbonyl group, an aralkyl group, or anaryl group, or R¹¹ and R¹² combine together to form a C₂ -C₆ alkylenechain, and, simultaneously or independently, R¹³ and R¹⁴ combinetogether to form a C₂ -C₆ alkylene chain, or R¹¹, R¹², R¹³ and R¹⁴combine together with the adjacent two carbon atoms to form asubstituted or unsubstituted aromatic cyclic group, a group of theformula: ##STR103## wherein X is an oxygen atom or a sulfur atom, Y isan oxygen atom, a sulfur atom, a protected or unprotected imino group ora methylene group, Z¹ and Z² are the same or different and each ahydrogen atom, a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, an aryl group or an aralkyl group, orboth combine at the end thereof to form a substituted or unsubstitutedalkylene group having 4 to 7 carbon atoms, and Ring A is a substitutedor unsubstituted benzene ring or a substituted or unsubstitutedheterocyclic ring having 1 to 4 hetero atoms selected from an oxygenatom, a sulfur atom and a nitrogen atom, and a group of the formula:##STR104## wherein X, Y and Ring A are the same as defined above, with acompound of the formula (II): ##STR105## wherein L¹ is a leaving groupand R⁴ is the same as defined above, in the presence of a base withoutusing a Lewis acid to give an azetidinone compound of the formula (III):##STR106## wherein R¹, R², R³ and R⁴ are the same as defined above,followed by subjecting the compound (III) to hydrolysis.
 3. A processaccording to claim 1, wherein said heterocyclic group is a memberselected from the group consisting ofa group of the formula: ##STR107##wherein X¹ is an oxygen atom or a sulfur atom, Y¹ is an oxygen atom, asulfur atom, a methylene group or an imino group substituted by an alkylgroup or an aryl group, and R¹¹, R¹², R¹³ and R¹⁴ are the same ordifferent and each a hydrogen atom, a C₁ -C₅ alkyl group, a cyano group,an alkoxycarbonyl group, an aralkyl group, or an aryl group, or R¹¹ andR¹² combine together to form a C₂ -C₆ alkylene chain, and,simultaneously or independently, R¹³ and R¹⁴ combine together to form aC₂ -C₆ alkylene chain, or R¹¹, R¹², R¹³ and R¹⁴ combine together withthe adjacent two carbon atoms to form a substituted or unsubstitutedaromatic cyclic group, and a group of the formula: ##STR108## wherein Xis an oxygen atom or a sulfur atom, Y is an oxygen atom, a sulfur atom,a protected or unprotected imino group or a methylene group, Z¹ and Z²are the same or different and each a hydrogen atom, a substituted orunsubstituted alkyl group, a substituted or unsubstituted cycloalkylgroup, an aryl group or an aralkyl group, or both combine at the endthereof to form a substituted or unsubstituted alkylene group having 4to 7 carbon atoms, and Ring A is a substituted or unsubstituted benzenering or a substituted or unsubstituted heterocyclic ring having 1 to 4hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogenatom.
 4. A process according to claim 1, wherein said heterocyclic groupis a group of the formula: ##STR109## wherein X is an oxygen atom or asulfur atom, Y is an oxygen atom, a sulfur atom, a protected orunprotected imino group or a methylene group, Z¹ and Z² are the same ordifferent and each a hydrogen atom, a substituted or unsubstituted alkylgroup, a substituted or unsubstituted cycloalkyl group, an aryl group oran aralkyl group, or both combine at the end thereof to form asubstituted or unsubstituted alkylene group having 4 to 7 carbon atoms,and Ring A is a substituted or unsubstituted benzene ring or asubstituted or unsubstituted heterocyclic ring having 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom.5. A process according to claim 1, wherein said heterocyclic group is agroup of the formula: ##STR110## wherein Ring B is a substituted orunsubstituted benzene ring, X is an oxygen atom or a sulfur atom, Y isan oxygen atom, a sulfur atom, a protected or unprotected imino group ora methylene group, and Z¹ and Z² are the same or different and each ahydrogen atom, a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, an aryl group or an aralkyl group, orboth combine at the end thereof to form a substituted or unsubstitutedalkylene group having 4 to 7 carbon atoms.
 6. A process according toclaim 1, wherein said heterocyclic group is a member selected from thegroup consisting of2,2-dimethyl-4-oxo-2,3-dihydro-4H-1,3-benzoxadin-3-yl;2,2-diethyl-4-oxo-2,3-dihydro-4H-1,3-benzoxadin-3-yl;2,2-diisopropyl-4-oxo-2,3-dihydro-4H-1,3-benzoxadin-3-yl;2,2-di-n-butyl-4-oxo-2,3-dihydro-4H-1,3-benzoxadin-3-yl;spiro[4-oxo-2,3-dihydro-4H-1,3-benzoxadin-2,1'-cyclohexan]-3-yl;2,2-dimethyl-4-thioxo-2,3-dihydro-4H-1,3-benzoxadin-3-yl;spiro[4-thioxo-2,3-dihydro-4H-1,3-benzoxadin-2,1'-cyclohexan]-3-yl; andspiro[4-oxo-2,3-dihydro-4H-1,3-benzothiazin-2,1'-cyclohexan]-3-yl.
 7. Aprocess according to claim 1, wherein the base has enough basicity tomake an enolate by removing a hydrogen atom at the α-position of saidalkanamide compound of the formula (I).
 8. A process according to claim3, wherein the base has enough basicity to make an enolate by removing ahydrogen atom at the α-position of said alkanamide compound of theformula (I).
 9. A process according to claim 4, wherein the base hasenough basicity to make an enolate by removing a hydrogen atom at theα-position of said alkanamide compound of the formula (I).
 10. A processaccording to claim 5, wherein the base has enough basicity to make anenolate by removing a hydrogen atom at the α-position of said alkanamidecompound of the formula (I).
 11. A process according to claim 6, whereinthe base has enough basicity to make an enolate by removing a hydrogenatom at the α-position of said alkanamide compound of the formula (I).12. A process according to claim 2, wherein said heterocyclic group is amember selected from the group consisting ofa group of the formula:##STR111## wherein X¹ is an oxygen atom or a sulfur atom, Y¹ is anoxygen atom, a sulfur atom, a methylene group or an imino groupsubstituted by an alkyl group or an aryl group, and R¹¹, R¹², R¹³ andR¹⁴ are the same or different and each a hydrogen atom, a C₁ -C₅ alkylgroup, a cyano group, an alkoxycarbonyl group, an aralkyl group, or anaryl group, or R¹¹ and R¹² combine together to form a C₂ -C₆ alkylenechain, and, simultaneously or independently, R¹³ and R¹⁴ combinetogether to form a C₂ -C₆ alkylene chain, or R¹¹, R¹², R¹³ and R¹⁴combine together with the adjacent two carbon atoms to form asubstituted or unsubstituted aromatic cyclic group, and a group of theformula: ##STR112## wherein X is an oxygen atom or a sulfur atom, Y isan oxygen atom, a sulfur atom, a protected or unprotected imino group ora methylene group, Z¹ and Z² are the same or different and each ahydrogen atom, a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, an aryl group or an aralkyl group, orboth combine at the end thereof to form a substituted or unsubstitutedalkylene group having 4 to 7 carbon atoms, and Ring A is a substitutedor unsubstituted benzene ring or a substituted or unsubstitutedheterocyclic ring having 1 to 4 hetero atoms selected from an oxygenatom, a sulfur atom and a nitrogen atom.
 13. A process according toclaim 2, wherein said heterocyclic group is a group of the formula:##STR113## wherein X is an oxygen atom or a sulfur atom, Y is an oxygenatom, a sulfur atom, a protected or unprotected imino group or amethylene group, Z¹ and Z² are the same or different and each a hydrogenatom, a substituted or unsubstituted alkyl group, a substituted orunsubstituted cycloalkyl group, an aryl group or an aralkyl group, orboth combine at the end thereof to form a substituted or unsubstitutedalkylene group having 4 to 7 carbon atoms, and Ring A is a substitutedor unsubstituted benzene ring or a substituted or unsubstitutedheterocyclic ring having 1 to 4 hetero atoms selected from an oxygenatom, a sulfur atom and a nitrogen atom.
 14. A process according toclaim 2, wherein said heterocyclic group is a group of the formula:##STR114## wherein Ring B is a substituted or unsubstituted benzenering, X is an oxygen atom or a sulfur atom, Y is an oxygen atom, asulfur atom, a protected or unprotected imino group or a methylenegroup, and Z¹ and Z² are the same or different and each a hydrogen atom,a substituted or unsubstituted alkyl group, a substituted orunsubstituted cycloalkyl group, an aryl group or an aralkyl group, orboth combine at the end thereof to form a substituted or unsubstitutedalkylene group having 4 to 7 carbon atoms.
 15. A process according toclaim 2, wherein said heterocyclic group is a member selected from thegroup consisting of2,2-dimethyl-4-oxo-2,3-dihydro-4H-1,3-benzoxadin-3-yl;2,2-diethyl-4-oxo-2,3-dihydro-4H-1,3-benzoxadin-3-yl;2,2-diisopropyl-4-oxo-2,3-dihydro-4H-1,3-benzoxadin-3-yl;2,2-di-n-butyl-4-oxo-2,3-dihydro-4H-1,3-benzoxadin-3-yl;spiro[4-oxo-2,3-dihydro-4H-1,3-benzoxadin-2,1'-cyclohexan]-3-yl;2,2-dimethyl-4-thioxo-2,3-dihydro-4H-1,3-benzoxadin-3-yl;spiro[4-thioxo-2,3-dihydro-4H-1,3-benzoxadin-2,1'-cyclohexan]-3-yl; andspiro[4-oxo-2,3-dihydro-4H-1,3-benzothiazin-2,1'-cyclohexan]-3-yl.
 16. Aprocess according to claim 2, wherein the base has enough basicity tomake an enolate by removing a hydrogen atom at the α-position of saidalkanamide compound of the formula (I).
 17. A process according to claim12, wherein the base has enough basicity to make an enolate by removinga hydrogen atom at the α-position of said alkanamide compound of theformula (I).
 18. A process according to claim 13, wherein the base hasenough basicity to make an enolate by removing a hydrogen atom at theα-position of said alkanamide-compound of the formula (I).
 19. A processaccording to claim 14, wherein the base has enough basicity to make anenolate by removing a hydrogen atom at the α-position of said alkanamidecompound of the formula (I).
 20. A process according to claim 15,wherein the base has enough basicity to make an enolate by removing ahydrogen atom at the α-position of said alkanamide compound of theformula (I).